Phosphorylation of Plk1 at S137 and T210 is Inhibited in Response to DNA Damage

Tsvetkov, Lyuben; Stern, David F.

doi:10.4161/cc.4.1.1348

Cited by 62 publications

(72 citation statements)

References 29 publications

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“…[31][32][33][34] Interestingly, it was suggested that mitotic DNA damage can lead to dephosphorylation of mitotically active Plk1 in a PP2A-dependent manner, 31 a conclusion that was, however, not supported by another report that found no dephosphorylation of Plk1 at Thr-210 or Ser-137 in response to mitotic DNA damage. 32 More importantly, activation of the DNA damage checkpoint in interphase prevents cells from entering mitosis, but the above studies did not address how Plk1 is regulated prior to mitotic entry. Plk1 can also be regulated by PP1, mediated by myosin phosphatase-targeting subunit 1 (MYPT).…”

Section: Discussionmentioning

confidence: 43%

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

et al. 2014

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These authors equally contributed to this work.Keywords: B55a, checkpoint recovery, DNA damage, Plk1, PP2AIn addition to governing mitotic progression, Plk1 also suppresses the activation of the G2 DNA damage checkpoint and promotes checkpoint recovery. Previous studies have shown that checkpoint activation after DNA damage requires inhibition of Plk1, but the underlying mechanism of Plk1 regulation was unknown. In this study we show that the specific phosphatase activity toward Plk1 Thr-210 in interphase Xenopus egg extracts is predominantly PP2A-dependent, and this phosphatase activity is upregulated by DNA damage. Consistently, PP2A associates with Plk1 and the association increases after DNA damage. We further revealed that B55a, a targeting subunit of PP2A and putative tumor suppressor, mediates PP2A/Plk1 association and Plk1 dephosphorylation. B55a and PP2A association is greatly strengthened after DNA damage in an ATM/ATR and checkpoint kinase-dependent manner. Collectively, we report a phosphatase-dependent mechanism that responds to DNA damage and regulates Plk1 and checkpoint recovery.

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Section: Discussionmentioning

confidence: 43%

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

et al. 2014

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“…Whether the centrosome also plays a central role in coordinating the mitotic arrest and reentry functions in mammalian cells in response to DNA damage is unclear. In response to DNA damage, Plk1 kinase activity and phosphorylation at Thr210 has been shown to be inhibited in an ATM/ ATR-Chk2/Chk1-dependent manner (62,69,73), while reactivation of Plk1 activity and T210 phosphorylation occurs upon recovery through an hBora:Aurora-A complex (45). Our finding that a centrosomally tethered form of Plk1 with reduced dynamic behavior impairs the ability of DNA damaged cells to reenter mitosis from G 2 arrest (Fig.…”

Section: Discussionmentioning

confidence: 54%

Functional Dynamics of Polo-Like Kinase 1 at the Centrosome

Kishi

Vugt

Okamoto

et al. 2009

Molecular and Cellular Biology

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Polo-like kinase 1 (Plk1) functions as a key regulator of mitotic events by phosphorylating substrate proteins on centrosomes, kinetochores, the mitotic spindle, and the midbody. Through mechanisms that are incompletely understood, Plk1 is released from and relocalizes to different mitotic structures as cells proceed through mitosis. We used fluorescence recovery after photobleaching to examine the kinetics of this process in more detail. We observed that Plk1 displayed a range of different recovery rates that differ at each mitotic substructure and depend on both the Polo-box domain and a functional kinase domain. Upon mitotic entry, centrosomal Plk1 becomes more dynamic, a process that is directly enhanced by Plk1 kinase activity. In contrast, Plk1 displays little dynamic exchange at the midbody, a process that again is modulated by the kinase activity of Plk1. Our findings suggest that the intrinsic kinase activity of Plk1 triggers its release from early mitotic structures and its relocalization to late mitotic structures. To assess the importance of Plk1 dynamic relocalization, Plk1 was persistently tethered to the centrosome. This resulted in a G 2 delay, followed by a prominent prometaphase arrest, as a consequence of defective spindle formation and activation of the spindle checkpoint. The dynamic release of Plk1 from early mitotic structures is thus crucial for mid-to late-stage mitotic events and demonstrates the importance of a fully dynamic Plk1 at the centrosome for proper cell cycle progression. This dependence on dynamic Plk1 was further observed during the mitotic reentry of cells after a DNA damage G 2 checkpoint, as this process was significantly delayed upon centrosomal tethering of Plk1. These results indicate that mitotic progression and control of mitotic reentry after DNA damage resides, at least in part, on the dynamic behavior of Plk1.

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“…The Aurora A/BORA/PLK1 pathway has emerged as an important positive regulator in facilitating recovery from the G2 checkpoint 22 . PLK1 is inactivated in response to IR by suppression of its T210 phosphorylation 23 . We observed an initial reduction (at 3 h post IR) in PLK1-T210 phosphorylation following cyclin F depletion.…”

Section: Resultsmentioning

confidence: 99%

Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

et al. 2015

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Cells respond to DNA damage by activating cell cycle checkpoints to delay proliferation and facilitate DNA repair. Here, to uncover new checkpoint regulators, we perform RNA interference screening targeting genes involved in ubiquitylation processes. We show that the F-box protein cyclin F plays an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein cyclin F with suppression of the B-Myb/cyclin A pathway to ensure a DNA damage-induced checkpoint response in G2.

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Phosphorylation of Plk1 at S137 and T210 is Inhibited in Response to DNA Damage

Cited by 62 publications

References 29 publications

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

Functional Dynamics of Polo-Like Kinase 1 at the Centrosome

Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

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